In murine S. japonicum infection, hepatic granuloma size, percent mice with esophageal varices, portal pressure, and immediate and delayed hypersensitivity to egg antigen (SEA) rise and then drop. Temporally correlated are rises and drops in some ongoing and/or SEA- and Con A-caused in vitro responses of spleen cells and intact granulomas. These in vitro reactions and in vivo granulomatous responses and portal hypertension were inhibited by serum from chronically infected mice (CMS). The in vitro response also were blocked by serum from acutely infected mice (AMS). It was postulated that during infection inhibitory factors produced in spleen and other organs accumulated in blood and regulated immune responses in granulomas and other sites. In support of this hypothesis, Con A inhibitory factor was found in SC cultures from 5 wk-infected mice and SEA-inhibitory factory (SIF) in SC cultures from 7 wk-infected mice. The SIF from CMS was in IgG-rich fractions (Sepharose CL-6B chromatography) and in an IgG1-rich fraction of CMS prepared by adherence to and elution from an anti-mouse Gamma globulin-Sepharose 4B column. These findings raised questions about these AMS, CMS and SC factors some of which we will investigate: 1. Further purification, specificity, and characterization of SIF. 2. Which organs besides spleen produce SIF, and when and for how long produced. 3. Whether SIF produced in cultures resembles SIF found in AMS and CMS. 4. Cellular and metabolic requirements for SIF production in culture. 5. Mechanisms of action of SIF, including their target cells. 6. If indicated by previous findings, the type and mechanisms of action of suppressor cells. These experiments should contribute much new information about mechanisms of immune regulation of the granuloma and immune responses in S. japonicum infection. They should help to answer questions about fundamental differences between immune regulation in S. mansoni and S. japonicum infections.